The abuse of cocaine and other stimulant drugs is a significant social and public health concern throughout the world (Crome, Drug Alcohol Dependence, 55:247, 1999). Drug abuse has contributed greatly to the increasing spread of HIV and HBV (Sorensen et al., Drug Alcohol Dependence, 59:17, 2000). Currently there are no efficacious medications for the treatment of cocaine abuse (Mendelson et al., N. Engl. J. Med., 334:965, 1996; Carroll et al., J. Med. Chem., 42:2721, 1999).
Although the mesolimblic dopamine pathway is believed to play a primary role in mediating the locomotor, discriminative stimulus, and reinforcing effects of cocaine (Smith et al., Drug Discovery Today, 2:322, 1999; Wingler, in “Cocaine Abuse: Behavior, Pharmacology and Clinical Application,” Higgens, S. T., Katz, J. L., Eds., Academic: San Diego, 1998, pp. 135-158, 1998; Kuhar et al., Trends Neurosci., 14:299, 1991; Ritz et al., Science, 237:1219, 1987), other neurotransmitter systems have also been implicated in the reinforcing effect of cocaine (Walsh et al., Psychopharmacology, 130:41, 1997; Rocha et al., Nature: Neuroscience, 1:132, 1998; Giros et al., Nature, 379:606, 1996; Rocha et al., Nature, 393:175, 1998; Witkin et al., Life Sci., 53:PL405, 1993; Dewey et al., Synapse, 30:119, 1998; Negus et al., Psychopharmacology, 152:398, 2000).
There is increasing evidence that opioid receptor agonists modulate the neurochemical and behavioral effects of cocaine. For example, kappa (κ) receptor agonists attenuate cocaine-induced increases in dopamine levels in the nucleus accumbens (Maisonneuve et al., Neurosci. Lett., 181:57, 1994; Heidbreder et al., NeuroReport, 5:1797, 1994). Administration of κ opioid receptor agonists has also been reported to attenuate the discriminative stimulus properties (Spealman et al., J. Pharmacol. Exp. Ther., 26:607, 1992; Spealman et al., Behav. Pharmacol., 5:21, 1994; Riberdy et al., Soc. Neurosci. Abstr., 21:718, 1995), conditioned reinforcing effects (Shippenberg et al., J. Pharmacol. Exp. Ther., 276:545, 1996; Shippenberg et al., Eur. J. Pharmacol., 345:27, 1998; Crawford et al., Psychopharmacology, 120:392, 1995), and self-administration of cocaine (Glick et al., Brain Res., 681:147, 1995; Mello et al., J. Pharmacol. Exp. Ther., 286:812, 1998; Schenk et al., Psychopharmacology, 144:339, 1999; Negus et al., J. Pharmacol. Exp. Ther., 282:44, 1997; Kuzmin et al., Eur. J. Pharmacol., 321:265, 1997). Further, κ opioid agonists have been reported to attenuate the reinstatement of extinguished drug-taking behavior in an animal model of relapse (Schenk et al., Psychopharmacology, 144:339, 1999; Schenk et al., Psychopharmacology, 151:85, 2000). Taken together, these findings suggest that activation of κ opioid receptors may functionally antagonize some abuse-related effects of cocaine, possibly by inhibiting the release of dopamine from dopaminergic neurons, and thus offers a novel and effective pharmacological approach to treat cocaine abuse.